Short report

Double trouble: managing diabetic emergencies

in patients with heart failure
In this paper Dr Legate Philip and Pathophysiology Left ventricular impairment may
Dr Ruth Poole look at the patho‑ Diabetes is a multi-system disorder develop regardless of typical risk
physiology and epidemiology of affecting many organs both at a factors such as hypertension and
heart failure in diabetes, heart macro- and microvasculature level. coronary artery disease in the
failure drugs and their effect on Hyperglycaemia, associated glycated diabetic population and this is
diabetes; also covered are practical proteins and dyslipidaemia damage termed diabetic cardiomyopa-
aspects of management of hyper‑ macrovasculature leading to athero- thy.21,22 The precise cause for this
glycaemic emergencies in diabetic sclerosis and risk of cardiovascular has not been determined, but
patients with heart failure. disease.4,13 Diabetes also affects may include mitochondrial dysfunc-
healthy endothelial function by loss tion, increased fibrosis, impaired
Introduction of inherent anti-atherogenic and calcium accumulation and inflam-
Heart failure and diabetes fre- anti-inflammatory properties which mation.21,23,24 There is also some
quently coexist and recent evidence in turn further accelerates athero- evidence that cardiac contractility
suggests a bidirectional relationship genicity and macrovascular dis- is affected by impaired cardiac glu-
with an increased risk of heart fail- ease.13,14 This effect in coronary cose metabolism and increased free
ure in patients with diabetes but arteries leads to the increased risk fatty acid oxidation for energy
also an increased risk of developing of myocardial infarction and ischae- metabolism; this in turn can lead to
diabetes in patients with heart fail- mic cardiomyopathy. Furthermore, ventricular impairment.25
ure.1,2 Although the management of comorbidities commonly seen in Recently, it has become apparent
heart failure in patients with stable patients with diabetes, such as hyper- that the relationship between heart
glycaemia is relatively straightfor- tension, dyslipidaemia and renal failure and diabetes is more bidirec-
ward, the management of the two impairment, also accelerate the pro- tional in nature rather than just
conditions becomes difficult during gression of cardiovascular disease. diabetes leading to heart failure.1,2 An
diabetic ketoacidosis (DKA) or The microcirculation has central observational study showed diabetes
hyperosmolar hyperglycaemic state (sympathetic and parasympathetic) developed in 29% of heart failure
(HHS). Diuretics and fluid restric- and local regulatory mechanisms.4 subjects compared with 18% of
tion are essential components of Endothelial dysfunction leads to matched control subjects over three
heart failure management while imbalance between the vasodilators years.26 One postulated theory is
aggressive intravenous fluid replace- and vasoconstrictors that it pro- that the decreased physical activity
ment is indicated in DKA and HHS. duces, leading to an inability to in heart failure patients may lead
promptly adjust the microvascular to decreased insulin sensitivity.2
Epidemiology flow to meet the metabolic needs of Furthermore, neuro-humoral activa-
The Framingham Heart Study3 the tissue.15 Subjects with diabetes tion, including increased catechola-
showed that diabetic men and have been found to have decreased mine levels and sympathetic activity
women were two and five times bioavailability of nitric oxide, a stimulate gluconeogenesis and gly-
more likely, respectively, to develop potent vasodilator, as well as cogenolysis leading to hyperglycae-
heart failure compared with control increased secretion of the vasocon- mia.27 Poor cardiac output and
subjects independent of age, hyper- strictor, endothelin-1.13,16,17 increased venous congestion can
tension, obesity, coronary artery Diabetic autonomic neuropathy cause hypoperfusion of the pancreas
disease and hyperlipidaemia. also leads to impaired autoregula- and the liver thereby weakening their
Data published as early as 2001 tion of blood flow.18 Diabetic potential to regulate metabolic home-
showed that every 1% (11mmol/mol) patients with disturbed autonomic ostasis.2 Indeed, results from a recent
increase in glycosylated haemoglobin function have a higher heart rate study suggest that left ventricular
(HbA1c) increased the risk of heart than non-diabetic patients due to assist devices improved glycaemic
failure by up to 10%.4–6 decreased vagal tone. Tachycardia control in patients with diabetes.28
In patients with chronic heart fail- increases myocardial oxygen
ure, the prevalence of diabetes is demand and reduces coronary Heart failure drugs and their
around 20%7–9 compared with 40% artery perfusion due to a shortened effect on blood glucose
in those hospitalised with worsening diastole which over time increases Diuretics
heart failure.10 There is evidence that the risk of arrhythmias and ventricu- Diuretics have a big role in symptom
hospitalised heart failure patients lar dysfunction.19 Cardiac auto- management of heart failure
with diabetes have a worse prognosis nomic dysfunction is also one of patients;29 however, studies have
with increased rates of cardiovascular the presumed causes of a ‘silent shown a positive association between
mortality and heart failure hospitalisa- myocardial infarction’ due to their diuretic use and the occurrence
tion post-discharge compared to decreased or even absent percep- of diabetes.30 Researchers have
patients without diabetes.11,12 tion of ischaemic pain.20 suggested many potential reasons

PRACTICAL DIABETES VOL. 35 NO. 4 COPYRIGHT © 2018 JOHN WILEY & SONS 139
Short report
Double trouble: managing diabetic emergencies in patients with heart failure

for this, which include hypokalae- sacubitril and valsartan) and ivabra- weakness, and weight loss can be
mia, changes in the autonomic dine have been shown to be effec- seen in both conditions. DKA
nervous system function, changes in tive in heart failure studies in patients usually present with vomit-
the beta-cell function and insulin patients with and without concomi- ing and abdominal pain.55
sensitivity as a result of diuretic tant diabetes.45,46 Heart failure patients with diabe-
use.2,31,32 Thiazides in particular tes are just as susceptible to develop-
have been shown to be associated Diabetes drugs and their effect ing these conditions as the rest of
with an increase in hyperglycae- on cardiac function the diabetic population. Some of
mia32 and therefore loop diuretics Glucose-lowering agents may pro- the common causes of DKA and
may be better tolerated in this group mote the development of heart HHS are infections, particularly
of patients. failure through several pathophysio- gastroenteritis; stress such as major
The symptoms of new-onset logical mechanisms related to surgery, myocardial infarction, pan-
diabetes, including polyuria, poly- increased insulin levels, water reten- creatitis or stroke; or insufficient
dipsia and weight loss in patients tion and low glucose availability for insulin.55 Previously undiagnosed
on diuretics, may be attributed to the myocardium. Tight glycaemic diabetes can present as DKA or
side effects of the diuretics them- control has not been shown to HHS. Certain medications such as
selves. This can delay diagnosis reduce incidence of heart failure in corticosteroids, thiazides, sympatho-
and potentially increase the risk of studies to date,5,47–49 while hypo­ mimetics, conventional and atypical
developing a diabetic emergency, glycaemia has been shown to be antipsychotic drugs can also precip-
particularly HHS. associated with worse outcomes.50 itate the development of DKA and
The thiazolidinediones lead to fluid HHS. It is important to note that
Beta blockers retention and, indeed, rosiglitazone no obvious cause of DKA and HHS
There have been concerns previ- was withdrawn because of the is identified in nearly one-fifth of
ously about beta blockers worsening increased risk of developing heart patients presenting with a hypergly-
glycaemic control and masking failure while taking it. Metformin51,52 caemic emergency.55
symptoms of hypoglycaemia;13,33 and empagliflozin53 have been The mainstay of treatment of
however, there have been no studies shown to be safe and effective in these diabetic emergencies is insu-
to date that prove this. On the other diabetic patients with heart failure lin, fluids and electrolyte correc-
hand, multiple studies have shown although caution needs to be exer- tion; ideally, these patients should
that beta-blockers improve survival cised when using metformin in also be managed in a high-care
and reduce heart failure hospitalisa- patients with renal impairment. setting. There are no specific
tions in patients with both diabetes The recent EMPA-REG OUTCOME guidelines to date on specific man-
and heart failure.34–36 There is some study has shown promising results agement of hyperglycaemic emer-
evidence that beta blockers can pre- with empaglifozin leading to signifi- gencies in heart failure although
cipitate diabetes especially when cant reduction in mortality and hos- UK guidelines suggest that ‘fluid
used alongside diuretics.4,6,32 Newer pitalisation from heart failure.53 replacement may need to be modi-
vasodilating beta blockers such as fied’.56 It is important to take a
carvedilol and nebivolol have less of Management of hyperglycaemic focused history from the patient or
an effect on glycaemic control.37 emergencies in patients with their family to try to identify what
heart failure might have triggered the decom-
Other medications commonly Diabetic ketoacidosis (DKA) and pensation. In addition to reviewing
used in heart failure hyperosmolar hyperglycaemic state the patient’s last HbA1c, it would be
ACE inhibitors (ACE-i) and angio- (HHS) are two acute and life-threat- helpful to find the patient’s latest
tensin II receptor blockers (ARBs) ening complications of diabetes echocardiogram, cardiology letter
are established therapies in heart requiring prompt recognition and and previous admission history as
failure. Randomised clinical trials aggressive therapy. If they have con- these may all give clues to their
have shown that they not only comitant heart failure, managing cardiac function, fluid status and
improve survival and reduce heart these patients may well pose many cardiac medication history. A weight
failure hospitalisation but can also challenges: managing haemody- taken in clinic may be helpful to
reduce incidence of new-onset dia- namic compromise; fluid manage- assess their current fluid depletion.
betes in heart failure patients.38–40 ment; and managing associated Assessing volume status in these
Mineralocorticoid receptor ant­ metabolic derangement such as patients can be difficult. Heart fail-
agonists (MRAs) have also shown kidney function, associated acidae- ure patients can have peripheral
prognostic benefits in heart failure mia and base excess. oedema and this does not reflect
studies.41,42 There have again been The development of DKA is usu- their intravascular volume. Patients
some concerns about the use of ally relatively acute, occurring in less are often intravascularly depleted
spironolactone (less so with eplen- than 24–48 hours, whereas HHS during the hyperglycaemic state
erone) and its effects on glycaemic usually develops over several days while appearing peripherally over-
control but there has been no con- to weeks and can lead to more loaded. Therefore care should be
clusive evidence to date and further profound dehydration.54 Symptoms taken while examining and inter-
studies are needed.43,44 Newer drugs such as polyuria, polydipsia, blurred preting volume status. Looking for
such as Entresto (a combination of vision, cognitive impairment, fatigue, jugular venous pressure, assessing

140 PRACTICAL DIABETES VOL. 35 NO. 4 COPYRIGHT © 2018 JOHN WILEY & SONS
 Short report
Double trouble: managing diabetic emergencies in patients with heart failure

the extent of peripheral oedema,

Practice points for fluid management in patients with heart failure presenting with
evidence of lung congestion (clini-
hyperglycaemic emergencies
cally and on X-ray), inferior vena
cava size and collapsibility on echo, • Fluid management can be difficult in these patients; accurate and recurrent assessment of
central venous pressure measure- fluid status is crucial
ment (if available), sensation of • Remember heart failure patients may appear peripherally overloaded while being
thirst and mucous membranes intravascularly depleted during the hyperglycaemic state
appearance can all help in assessing • Previous records of weight, echo findings and fluid status may be helpful
volume status. Haemodynamic • Normal saline with potassium is the fluid of choice
status can be assessed by blood pres- • A more cautious approach of giving 1–1.5 litres of normal saline over 1–2 hours with
sure/mean arterial pressure and frequent haemodynamic and clinical monitoring could be attempted as initial
assessment of end-organ perfusion resuscitation in patients with heart failure
(urine output, conscious level, • Fluid resuscitation should be tailored to patients’ clinical status and response. If there are
capillary refill time). It is important signs of worsening haemodynamics, then this might warrant use of vasoactive drugs and
to remember that some of these escalation of treatment to a critical care setting
patients have a chronically low
blood pressure due to reduced required is the preferred fluid in targets with only half of the volume
cardiac output and effects of medi- both DKA56 and HHS,54 as the main infused. However, more concen-
cations; therefore looking at their electrolyte losses are of sodium, trated dextrose infusions can be an
baseline blood pressure reading chloride and potassium. A Cochrane irritant to veins so this needs to be
from clinic letters may guide assess- review recommended use of crystal- done through a large vein such as in
ment. A high urine output reflects loid fluids rather than colloid in the ante-cubital fossa rather than
the hyperglycaemia and does not ill patients.57 The use of Ringer’s the back of the hand or ideally
mean the patient is well hydrated. lactate (Hartmann’s solution) in through a central venous catheter.
A low urine output suggests poor HHS54 or in DKA58 failed to show
renal perfusion. Blood tests may benefit compared to normal saline. Renal impairment
include venous blood glucose, In patients with heart failure a Blood tests in these patients may
ketones, blood gas, serum osmolal- more cautious approach is required. reveal renal impairment. This could
ity (calculated or measured) and Giving 1–1.5 litres of normal saline be due to many reasons including
troponin if clinically indicated. The over 1–2 hours with frequent haemo- diabetic nephropathy, heart failure
role of brain natriuretic peptide dynamic and clinical monitoring (i.e. cardio-renal syndrome), dehy-
(BNP) in these situations would be could be attempted as initial resusc­ dration and medications. It is
difficult to interpret and as such itation. Further fluid resuscitation important to go through previous
there is no role currently in BNP should be tailored to the patient’s results and identify baseline renal
guided management. An ECG clinical status and response. If there function. Depending on the degree
should be performed in all patients. are signs of worsening haemodynam- of derangement and clinical assess-
ics, for example low blood pressure or ment, it may be necessary to with-
Specific management of evidence of poor perfusion such as hold some of the prognostic heart
associated abnormalities cool peripheries or poor urine out- failure medications such as ACE-i
Fluid balance put, then this might warrant use of and MRAs and adjust diuretics to
Both DKA and HHS are associated vasoactive drugs and escalation of aid patients’ recovery from the acute
with large fluid and electrolyte defi- treatment to a critical care setting. phase. Measuring urine output and
cits. The severity of dehydration is It is also important to keep in mind recording daily weights (if possible)
greater in HHS than in DKA. Fluid that non-cardiogenic pulmonary further aids management. When the
replacement is crucial for the resto- oedema55 can develop in DKA patient is stable and over the acute
ration of intravascular, interstitial patients from excessive fluid replace- phase, it is important to restart and
and intracellular volume and renal ment or capillary-alveolar leaks (adult to up-titrate these drugs to target
perfusion. The average fluid deficit respiratory distress syndrome) even doses as tolerated. The hospital heart
is approximately 5–7 litres in DKA56 in patients without renal or cardiac failure team should be involved in
but may be as much as 22 litres in problems. This can further compli- the patient’s management as soon
HHS.54 For DKA, UK guidelines cate fluid resuscitation and manage- as possible.
suggest one litre of fluid over the ment; fortunately, this is a relatively
first hour then 500ml/hour over the rare complication.56 Metabolic derangement
next 4 hours.56 In HHS, the guide- In DKA, once glucose has fallen It is important to remember acidosis
lines suggest replacing half of the to target levels but where ketones/ and acidaemia are cardiac suppres-
fluid deficit in the first 12 hours acidosis have not yet resolved, a sants.59 Some degree of acidosis can
and the other half in the following 10% dextrose infusion is usually be seen in HHS and DKA patients
12 hours.54 Such large volume commenced to prevent hypoglycae- owing to their poor cardiac output,
administration can decompensate mia.56 In patients with heart failure increased anaerobic metabolism,
heart failure patients. where fluid overload is becoming a glucose and ketones, metformin,
Normal saline (0.9% sodium worry, this can be substituted with poor renal function and liver hypo­
chloride) with potassium added as 20% dextrose to maintain glycaemic perfusion. It is also important that

PRACTICAL DIABETES VOL. 35 NO. 4 COPYRIGHT © 2018 JOHN WILEY & SONS 141
Short report
Double trouble: managing diabetic emergencies in patients with heart failure

care be taken in correcting acidosis potentially contribute to worse out- 11. Gustafsson I, et al.; Danish Investigations of
gently, if hyperglycaemia is the comes than those without comorbid Arrhythmia and Mortality on Dofetilide Study
Group. Influence of diabetes and diabetes-gender
primary cause of the acidosis. diabetes. Hyperglycaemic emergen- interaction on the risk of death in patients hospi-
Bicarbonate should not be given to cies such as DKA and HHS are talized with congestive heart failure. J Am Coll
correct the metabolic derangement associated with a high mortality risk. Cardiol 2004;43(5):771–7.
12. Dries DL, et al. Prognostic impact of diabetes mel-
as it can worsen central nervous Managing such acute emergencies litus in patients with heart failure according to
system acidosis and precipitate in patients with diabetes and heart the etiology of left ventricular systolic dysfunction.
cerebral oedema.56 failure can be challenging, part­ J Am Coll Cardiol 2001;38(2):421–8.
icularly in assessing fluid status 13. Kasznicki J, Drzewoski J. Heart failure in the dia-
betic population – pathophysiology, diagnosis
Electrolyte imbalance correctly. It is important to involve and management. Arch Med Sci 2014;10(3):
Abnormalities in sodium and potas- both diabetologists and cardiologists 546–56.
sium are common. This can be as soon as possible to ensure the best 14. Celermajer DS. Endothelial dysfunction: does it
matter? Is it reversible? J Am Coll Cardiol
because of the volume status and outcome for patients. 1997;30(2):325–33.
acute shifts between intra- and extra- 15. Quiñones MJ, et al. Coronary vasomotor abnor-
cellular spaces in hyperglycaemic Dr Legate Philip,1 Speciality malities in insulin-resistant individuals. Ann Intern
Med 2004;140(9):700–8.
states. However, in patients with Registrar, Cardiology 16. Kasznicki J, et al. Evaluation of oxidative stress
heart failure medications such as Dr Ruth Poole,1 Consultant, markers in pathogenesis of diabetic neuropathy.
ACE-i, diuretics and MRAs can also Diabetes & Endocrinology Mol Biol Rep 2012;39(9):8669–78.
be causative. Often the admission 17. Kalani M. The importance of endothelin-1 for
1Poole microvascular dysfunction in diabetes. Vasc Health
sodium is low because of the hyper­ Hospital NHS Trust, Poole, Risk Manag 2008;4(5):1061–8.
glycaemia. Modern analysers do Dorset, UK 18. Campbell IW, et al. The natural history of diabetic
not give pseudo-hyponatraemia with autonomic neuropathy. Horm Metab Res Suppl
1980;9:61–7.
hyperlipidaemia but the low sodium Correspondence to: Dr Ruth Poole, 19. Ewing DJ, et al. Autonomic neuropathy, QT interval
with hyperglycaemia is real in order Consultant, Diabetes & lengthening, and unexpected deaths in male dia-
to preserve osmolality. As a result, a Endocrinology, Poole Hospital betic patients. Diabetologia 1991;34(3):182–5.
normal or high measured serum Foundation Trust, Longfleet Road, 20. Niakan E, et al. Silent myocardial infarction and
diabetic cardiovascular autonomic neuropathy.
sodium in this setting indicates a Poole BH15 2JB; email: Ruth. Arch Intern Med 1986;146(11):2229–30.
severe state of dehydration, as is Poole@poole.nhs.uk 21. Marwick TH. Diabetic heart disease. Postgrad Med
often the case in patients presenting J 2008;84(990):188–92.
22. Rutter MK, et al. Impact of glucose intolerance and
with HHS. Similarly, an extracellular Declaration of interests insulin resistance on cardiac structure and function:
shift of potassium caused by insulin There are no conflicts of interest sex-related differences in the Framingham Heart
deficiency, acidaemia and hyper- declared. Study. Circulation 2003;107(3):448–54.
23. Zhao S-M, et al. Progressive decay of Ca2+ home-
tonicity may increase the patient’s ostasis in the development of diabetic cardiomyo-
serum potassium. However, a high References pathy. Cardiovasc Diabetol 2014;13(1):75.
measure of serum potassium in this 1. Campbell P, et al. The bi-directional impact of two 24. Kawaguchi M, et al. A comparison of ultrastruc-
setting may be falsely reassuring as chronic illnesses: heart failure and diabetes – a tural changes on endomyocardial biopsy speci-
review of the epidemiology and outcomes. Card mens obtained from patients with diabetes melli-
the body’s total potassium stores may Fail Rev 2015;1(1):8–10. tus with and without hypertension. Heart Vessels
in reality be depleted. Renal impair- 2. Tousoulis D, et al. Diabetes mellitus and heart fail- 1997;12(6):267–74.
ment and heart failure medications ure. Eur Cardiol Rev 2014;9(1):37–42. 25. Rosano GMC, et al. Metabolic therapy for patients
3. Kannel WB, et al. Role of diabetes in congestive with diabetes mellitus and coronary artery dis-
such ACE-i, ARBs and MRAs can also heart failure: the Framingham study. Am J Cardiol ease. Am J Cardiol 2006;98(5):14–8.
cause hyperkalaemia. A low potas- 1974;34(1):29–34. 26. Amato L, et al. Congestive heart failure predicts
sium level therefore suggests severe 4. Dokken BB. The pathophysiology of cardiovas- the development of non-insulin-dependent diabe-
cular disease and diabetes: beyond blood tes mellitus in the elderly. The Osservatorio
total body potassium depletion. pressure and lipids. Diabetes Spectr 2008; Geriatrico Regione Campania Group. Diabetes
21(3):160–5. Metab 1997;23(3):213–8.
Thromboembolic state 5. Stratton IM, et al. Association of glycaemia with 27. Heck PM, Dutka DP. Insulin resistance and heart
During the acute phase of a hyper­ macrovascular and microvascular complications of failure. Curr Heart Fail Rep 2009;6(2):89–94.
type 2 diabetes (UKPDS 35): prospective observa- 28. Guglin M, et al. Improvement in blood glucose
glycaemic emergency, patients tional study. BMJ 2000;321(7258):405–12. control in patients with diabetes after implanta-
are at risk of clot formation due 6. Iribarren C, et al. Glycemic control and heart tion of left ventricular assist devices. ASAIO J
to the associated hyper-viscosity of failure among adult patients with diabetes. 2014;60(3):290–3.
Circulation 2001;103(22):2668–73. 29. McMurray JJ, et al.; the ESC Committee for
blood. This is further worsened 7. Hamby RI, et al. Diabetic cardiomyopathy. JAMA Practice Guidelines. ESC Guidelines for the diag-
by poor cardiac output in patients 1974;229(132):1749–54. nosis and treatment of acute and chronic heart
with concomitant heart failure. 8. Shindler DM, et al. Diabetes mellitus, a predictor failure 2012: The Task Force for the Diagnosis and
Therefore thromboembolism pro­ of morbidity and mortality in the Studies of Left Treatment of Acute and Chronic Heart Failure
Ventricular Dysfunction (SOLVD) Trials and 2012 of the European Society of Cardiology.
phylaxis should be administered Registry. Am J Cardiol 1996;77(11):1017–20. Developed in collaboration with the Heart Failure
in all patients unless there is a 9. Cohn JN, et al. A comparison of enalapril with Association (HFA) of the ESC. Eur Heart J
significant contraindication. hydralazine-isosorbide dinitrate in the treatment 2012;33(14):1787–847.
of chronic congestive heart failure. N Engl J Med 30. Elliott WJ, Meyer PM. Incident diabetes in clinical
1991;325(5):303–10. trials of antihypertensive drugs: a network
Summary 10. Greenberg BH, et al. Influence of diabetes on charac- meta-analysis. Lancet 2007;369(9557):201–7.
Patients with concomitant heart teristics and outcomes in patients hospitalized with 31. Plavinik FL, et al. Hypokalemia, glucose intoler-
heart failure: A report from the Organized Program to ance, and hyperinsulinemia during diuretic
failure and diabetes have diverse Initiate Lifesaving Treatment in Hospitalized Patients therapy. Hypertension 1992;19(2 Suppl):1126–9.
pathophysiological, metabolic and with Heart Failure (OPTIMIZE-HF). Am Heart J 32. Luna B, Feinglos MN. Drug-Induced hyperglyce-
neuro-hormonal abnormalities that 2007;154(2):277.e1–8. mia. JAMA 2001;286(16):1945–8.

142 PRACTICAL DIABETES VOL. 35 NO. 4 COPYRIGHT © 2018 JOHN WILEY & SONS
 Short report
Double trouble: managing diabetic emergencies

33. Mills GA, Horn JR. Beta-blockers and glucose control. Drug Intell Clin Pharm
1985;19(4):246–51.
34. Haas SJ, et al. Are β-blockers as efficacious in patients with diabetes mellitus
as in patients without diabetes mellitus who have chronic heart failure?
A meta-analysis of large-scale clinical trials. Am Heart J 2003;146(5):848–53.
35. Domanski M, et al.; BEST Investigators. The effect of diabetes on outcomes
of patients with advanced heart failure in the BEST trial. J Am Coll Cardiol
2003;42(5):914–22.
36. Deedwania PC, et al.; MERIT-HF Study Group. Efficacy, safety and tolerability of
metoprolol CR/XL in patients with diabetes and chronic heart failure: Experiences
from MERIT-HF. Am Heart J 2005;149(1):159–67.
37. Bakris GL, et al.; GEMINI Investigators. Metabolic effects of carvedilol vs meto-
prolol in patients with type 2 diabetes mellitus and hypertension. JAMA
2004;292(18):2227–36.
38. Vermes E, et al.; Studies Of Left Ventricular Dysfunction. Enalapril reduces
the incidence of diabetes in patients with chronic heart failure: insight
from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003;
107(9):1291–6.
39. Yusuf S, et al.; Candesartan in Heart Failure – Assessment of Reduction in
Mortality and Morbidity Program Investigators. Effects of candesartan on the
development of a new diagnosis of diabetes mellitus in patients with heart fail-
ure. Circulation 2005;112(1):48–53.
40. Young JB, et al.; Candesartan in Heart failure Assessment of Reduction in
Mortality and morbidity (CHARM) Investigators and Committees. Mortality and
morbidity reduction with candesartan in patients with chronic heart failure and
left ventricular systolic dysfunction: Results of the CHARM low-left ventricular
ejection fraction trials. Circulation 2004;110(17):2618–26.
41. Pitt B, et al. The effect of spironolactone on morbidity and mortality in patients
with severe heart failure. N Engl J Med 1999;341(10):709–17.
42. Zannad F, et al.; EMPHASIS-HF Study Group. Eplerenone in patients
with systolic heart failure and mild symptoms. N Engl J Med 2011;364(1):
11–21.
43. Swaminathan K, et al. Spironolactone for poorly controlled hypertension in type 2
diabetes: conflicting effects on blood pressure, endothelial function, glycaemic
control and hormonal profiles. Diabetologia 2008;51(5):762–8.
44. Yamaji M, et al. Effect of eplerenone versus spironolactone on cortisol and
hemoglobin A1c levels in patients with chronic heart failure. Am Heart J
2010;160(5):915–21.
45. National Institute for Health and Care Excellence. Sacubitril valsartan for treat-
ing symptomatic chronic heart failure with reduced ejection fraction. Technology
appraisal guidance [TA388]. National Institute for Health and Care Excellence,
April 2016.
46. National Institute for Health and Care Excellence. Chronic heart failure in adults:
management. Clinical guidance [CG108]. National Institute for Health and Care
Excellence, August 2010.
47. Elder DH, et al. Mean HbA1c and mortality in diabetic individuals with heart
failure: a population cohort study. Eur J Heart Fail 2016;18(1):94–102.
48. Goode KM, et al. Elevated glycated haemoglobin is a strong predictor of mortal-
ity in patients with left ventricular systolic dysfunction who are not receiving
treatment for diabetes mellitus. Heart 2009;95(11):917–23.
49. Aguilar D, et al. Relationship of hemoglobin A1c and mortality in heart failure
patients with diabetes. J Am Coll Cardiol 2009;54(5):422–8.
50. Ukena C, et al. Hypo- and hyperglycemia predict outcome in patients with left
ventricular dysfunction after acute myocardial infarction: Data from EPHESUS.
J Card Fail 2012;18(6):439–45.
51. MacDonald MR, et al. Treatment of type 2 diabetes and outcomes in patients
with heart failure: A nested case-control study from the U.K. General Practice
Research Database. Diabetes Care 2010; 33(6):1213–8.
52. Boussageon R, et al. Reappraisal of metformin efficacy in the treatment of type
2 diabetes: A meta-analysis of randomised controlled trials. PLoS Med 2012;
9(4):e1001204.
53. Zinman B, et al.; EMPA-REG OUTCOME Invest­igators. Empagliflozin, cardiovas-
cular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373(22):
2117–28.
54. Scott A, Claydon A; Joint British Diabetes Societies Inpatient Care Group. The
management of the hyperosmolar hyperglycaemic state (HHS) in adults with
diabetes. NHS Diabetes, August 2012.
55. Lupsa B, Inzucchi S. Diabetic ketoacidosis and hyperosmolar hyperglycaemic syn-
drome. In Endocrine emergencies: Recognition and treatment. Loriaux L (ed).
Springer, 2014; pp 15–31.
56. Dhatariya K, Savage M; Joint British Diabetes Societies Inpatient Care Group. The
management of diabetic ketoacidosis in adults, 2nd edn. NHS Diabetes,
September 2013.
57. Perel P, et al. Colloids versus crystalloids for fluid resuscitation in critically ill patients.
Cochrane Database Syst Rev 2013;(2):CD000567. doi: 10.1002/14651858.CD000567.
pub6. PMID: 23450531.
58. Van Zyl DG, et al. Fluid management in diabetic-acidosis – Ringer’s lactate ver-
sus normal saline: a randomized controlled trial. QJM 2012;105(4):337–43.
59. Poole-Wilson PA. Acidosis and contractility of heart muscle. Ciba Found Symp
1982;87:58–76.

COPYRIGHT © 2018 JOHN WILEY & SONS 143